Vaccine-induced cellular immunity can control viral replication in simian immunodeficiency virus (SIV)-infected monkeys, though the level and persistence of viral control is not optimal. We previously demonstrated that immunization of monkeys with plasmid DNA followed by replication defective adenoviral vectors encoding SIV proteins led to a reduction in viremia and prolonged survival. This survival was associated with preserved central memory CD4+ T lymphocytes and could be predicted by the magnitude of the vaccine-induced cellular immune response. These immune correlates of vaccine efficacy should guide the evaluation of AIDS vaccines in humans. In addition, the results of the this study indicated that set point viral load and total CD4+ T lymphocyte count may not be fully predictive of a vaccine effect. The studies described above used a combination of several SIV antigens: Env, Gag and Pol. In an ongoing study, we immunized monkeys with this same combination, or with Env alone, or Gag-Pol alone, to determine the individual effect of each vaccine immunogen. The results indicate that both Gag-Pol and Env contribute to a protective effect on viral load and that these effects are most likely T-cell mediated. The combination of Env plus Gag-Pol worked better than either alone. Other ongoing studies will test the effect of several alternative serotypes of recombinant adenovirus In addition, we are currently performing studies to develop a low dose mucosal challenge model for SIV - which may be a more physiological model of human HIV infection